key: cord-271495-5906wju4
authors: Beldomenico, Pablo M.
title: Do superspreaders generate new superspreaders? a hypothesis to explain the propagation pattern of COVID-19
date: 2020-05-11
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.05.025
sha: 
doc_id: 271495
cord_uid: 5906wju4

Abstract The current global propagation of COVID-19 is heterogeneous, with slow transmission continuing in many countries, and exponential propagation in others, in which the time that took to begin this explosive spread varies greatly. It is proposed that this could be explained by cascading superspreading events, in which new infections caused by a superspreader are more likely to be highly infectious. The mechanism suggested for this is related to viral loads. Exposure to high viral loads may result in infections of high intensity, which exposes new cases to high viral loads, and so on. This notion is supported by experimental veterinary research.

J o u r n a l P r e -p r o o f 3 ---

The patterns of propagation of the Severe Acute Respiratory Syndrome (SARS) outbreak of 2003 were not explained by conventional epidemic models that assumed homogeneity of infectiousness. Instead, the existing datasets were best matched by models that used negative binomial distributions in which a small proportion of cases were highly infectious (Lloyd-Smith et al., 2005 , McDonald et al., 2004 , Shen et al., 2003 . Data and modelling supported the existence of 'superspreaders' which played a crucial role in propagating the disease by being very efficient at transmitting SARS-CoV-1, such that in the absence of superspreading events most cases infected few, if any, secondary contacts (Stein, 2011) . Almost a decade later emerged the Middle East Respiratory Syndrome coronavirus (MERS-CoV), with analogous infection dynamics involving superspreading events (Hui, 2016) . Similarly, early modelling and data suggested that a small proportion of cases of COVID-19 were responsible for most transmission, which is evidence that superspreaders also play an important role for SARS-CoV-2 (MacKenzie D, 2020, Frieden and Lee, 2020). Explanations of this superspreader status included high viral shedding due to poor immunocompetence, underlying diseases or co-infection, or elevated contact rate due active social behaviour (Lloyd-Smith et al., 2005 , McDonald et al., 2004 , Shen et al., 2003 , Wong et al. 2015 .

The propagation of SARS-CoV-2 has shown to be heterogeneous at a global scale (data publicly shared by the World Health Organization and Johns Hopkins University). After the virus started to be reported outside of China, cases were infecting fewer people than expected, compared to the rate of spread in China. By the end of February, over 50 countries outside China had confirmed the infection, but only three of these, South Korea, Italy and Iran, presented notable spread. In South Korea, during the first month of viral propagation there were only two to three reports of new infections per day. However, the rapid spread began after one case was linked to 3900 secondary cases in Daegu (Shim et al., 2020) .

In Italy, the rapid surge of cases began in a cluster in Lombardy after an infected man was hospitalised without precautionary measures and infected other patients (mostly elder people) and health workers.

Apparently, there was no calm period in Iran, where the first two reported cases were fatal, two weeks later there were 1500 cases, and after one month there were over 17000 reported infections. A few weeks later, several other countries underwent a similar exponential growth in the number of cases, despite many of them taking drastic measures to control the epidemic. A notable case was the USA, Page 5 of 10 J o u r n a l P r e -p r o o f 4 where the infection was propagating slowly since January 20th until early March, when the daily growth in the number of cases went suddenly from being of one digit to surpassing 30%, remaining above that geometrical growth rate for almost 20 days. This explosive spread began in New York City, where the number of cases reached 20000 in just over two weeks. In contrast, in most countries the infection has been propagating at a slow to moderate pace (e.g. Thailand, Singapore, Egypt, Finland, Japan, Australia, among many others). In general, there have been also contrasts in the apparent case-fatality rate (deaths/reported) depending on the speed of propagation, being much lower in countries with slow spread (e.g. 0.1 % in Singapore, 1.4% in Australia, 1.8% in Thailand) compared with those where the transmission was notably high (e.g. 14% in Italy, 12% in Spain, 7% in USA). This difference might be too large to be explained solely by detection bias.

It appears that within a region SARS-CoV-2 spreads gradually unless a chain reaction of transmission is triggered. Independent superspreading events due to individual variation cannot explain this large-scale heterogeneous pattern of transmission. The occurrence of superspreaders may not be at random and may depend on other superspreaders. It is proposed that infections caused by contact with superspreaders are more likely to result in new superspreaders than those caused by transmission from a less infectious individual. The mechanism by which this would be possible is by exposure to differential viral load. The primary mode of transmission of SARS-CoV-2 appears to be through exposure to respiratory droplets and direct contact with infected individuals and their contaminated environment (Xiao et al., 2017; van Doremalen et al., 2020) . Droplets may contain a few or a million viral particles, and this differential load determines how much the environment is contaminated and the infective dose a susceptible person is exposed to. A case with a high intensity of infection has the potential of being a superspreader due to high viral shedding. Susceptible people exposed to this hypothetical superspreader would be exposed to a high viral dose. Infections resulting from exposure to high loads of virus are expected to be of high intensity, as a large quantity of viral particles initiating replication in synchrony might overwhelm the mechanisms of resistance, and the poor control of viral replication may therefore result in a new potential superspreader. This hypothesis has support from veterinary research.

For example, in a recent study calves were experimentally infected by Bovine Viral Diarrhoea virus (an J o u r n a l P r e -p r o o f 5 outcome of infection was dose dependent with animals given a higher dose developing severe disease and more pronounced viral replication and shedding. Moreover, sentinel calves housed with the lowdose-infected group did not become infected, despite viral shedding being confirmed. Other experimental infections also found that viral dose correlated positively with disease severity and viral shedding in other virus-domestic animal systems, such as Feline Viral Rhinotracheitis in cats (Gaskell and Povey, 2008) , Low Pathogenic Avian Influenza virus in chicken (Zarkov and Bochev, 20) , and Equine Influenza in ponies (Mumford et al., 1990) .

Under the hypothesis posited here, cases with low-to-moderate intensity of infection would mainly yield new infections of low-to-moderate severity and viral shedding in people who are not in risk groups.

replication, generating a 'domino effect'. The severity of the disease caused by high viral loads is expected to be high. This would be due to extensive cell damage caused by large amounts of virus and also due to the resulting immune response. The virulence arising from an infection by SARS-CoV-2 is related to inflammatory self-damage (Quin et al., 2020) , and it is expected that an infection initiated by a large number of viral particles would generate a stronger immune response, compared to infections caused by a low viral dose. Therefore, a case resulting from an exposure to high viral loads has the potential to develop severe disease and also of being highly infectious. It was found that in MERS patients the severity of the disease was positively correlated with viral load (Min et al., 2016) , and the same was recently reported for COVID-19 2020; Zou et al., 2020) .

It could be argued that individuals with higher viral loads are more likely to be hospitalised or die, and therefore would be less likely to contribute to community transmission as superspreaders. However, it should be taken into account that the outcome of an exposure to a high viral dose will largely depend on the tolerance (ability to reduce the damage of an infection) of an individual (Råberg et al., 2009) . Given equal resistance (ability to limit the infection), exposure to high viral loads will result in severe disease in the less tolerant and high infection intensity with few manifestations in the more tolerant. The latter case is of special concern, because in these individuals the clinical signs would be mild or absent, and therefore are likely to be undetected, exposing many people to high viral loads. On the other hand, severe cases may be important sources of disease in hospitals . For example, in J o u r n a l P r e -p r o o f 6 Argentina, 17% of the cases reported to date are healthcare workers (Infobae, 2020) . Therefore, the presence of superspreaders in hospitals could make them nodes where cascades of superspreading events emerge, which is consistent with what was observed in Lombardy.

Disease is traditionally studied as a binary outcome, infected or non-infected. The concepts presented here alert us to the value of studying disease as a continuous variable (i.e. infection intensity) (Beldomenico and Begon, 2010) . Measuring the intensity of an infection is crucial because it may be related to the virulence as well as the infectiousness. There are many studies of different viral diseases in which the length of viral shedding is recorded, yet very few produced data on the viral shedding load.

The hypothesis posited here needs to be tested by empirical and theoretical studies, but this requires that data on viral load (viraemia and shedding) are urgently collected. If superspreaders generate new superspreaders by exposing susceptible people to large viral loads, this mechanism should be immediately acknowledged and considered in the responses being undertaken. In particular, emphasis should be placed on the isolation or strict distancing of people of risk groups, as they would not only have more chances of developing a more severe disease (with the potential of overwhelming the health system), but they could also be source of high viral loads. In addition, aggressive contact tracing and testing would allow quick identification of tolerant superspreaders, who might be key elements of propagation.

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